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Epidemiology and Psychiatric Sciences Nov 2022Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are... (Review)
Review
AIMS
Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates.
METHOD
We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons.
RESULTS
One hundred twocountries were included, from Europe ( = 35), Asia ( = 24), Africa ( = 20), South America ( = 11), North America ( = 7) and Oceania and Australia ( = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association ( = 0.43, < 0.001) between a country's Stringency Index and healthcare expenditure per capita.
CONCLUSIONS
Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.
Topics: Humans; Clozapine; Antipsychotic Agents; Neutropenia; Psychotic Disorders; Australia
PubMed: 36426600
DOI: 10.1017/S204579602200066X -
Genes Aug 2023PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, previously known as... (Review)
Review
PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, previously known as Hyperzincemia/Hypercalprotectinemia (Hz/Hc) syndrome, is a recently described, rare auto-inflammatory disorder caused by specific deleterious variants in the gene (p.E250K and p.E257K). The disease is characterized by chronic systemic inflammation, cutaneous and osteoarticular manifestations, hepatosplenomegaly, anemia, and neutropenia. Increased blood levels of MRP 8/14 and zinc distinguish this condition from other PSTPIP1-associated inflammatory diseases (PAID). The aim of this systematic review is to provide a comprehensive overview of the disease phenotype, course, treatment, and outcome based on reported cases. This systematic review adheres to the PRISMA guidelines (2020) for reporting. A literature search was performed in Embase, Medline, and Web of Science on 13 October 2022. The quality of the case reports and case series was assessed using the JBI checklists. Out of the 43 included patients with PAMI syndrome, there were 24 females and 19 males. The median age at onset was 3.9 years. The main clinical manifestations included anemia (100%), neutropenia (98%), cutaneous manifestations (74%), osteoarticular manifestations (72%), splenomegaly (70%), growth failure (57%), fever (51%), hepatomegaly (56%), and lymphadenopathy (39%). Systemic inflammation was described in all patients. Marked elevation of zinc and MRP 8/14 blood levels were observed in all tested patients. Response to treatment varied and no consistently effective therapy was identified. The most common therapeutic options were corticosteroids (N = 30), anakinra (N = 13), cyclosporine A (N = 11), canakinumab (N = 6), and anti-TNF (N = 14). Hematopoietic stem cell transplantation has been recently reported to be successful in five patients. Our review highlights the key characteristics of PAMI syndrome and the importance of considering this disease in the differential diagnosis of patients presenting with early-onset systemic inflammation and cytopenia.
Topics: Female; Male; Humans; Tumor Necrosis Factor Inhibitors; Neutropenia; Diagnosis, Differential; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing
PubMed: 37628706
DOI: 10.3390/genes14081655 -
Journal For Immunotherapy of Cancer Jun 2023Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic...
BACKGROUND
Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown. Here we examined patients with pancreatic cancer, a disease known to induce myeloid-derived suppressor cells (MDSCs), and for which pegfilgrastim is routinely administered concurrently with FOLFIRINOX but not with gemcitabine-based chemotherapy regimens.
METHODS
Serial blood was collected from patients with pancreatic ductal adenocarcinoma newly starting on FOLFIRINOX or gemcitabine/n(ab)paclitaxel combination chemotherapy regimens. Neutrophil and monocyte frequencies were determined by flow cytometry from whole blood and peripheral blood mononuclear cell fractions. Serum cytokines were evaluated pretreatment and on-treatment. Patient serum was used in vitro to differentiate healthy donor monocytes to MDSCs as measured by downregulation of major histocompatibility complex II (HLA-DR) and the ability to suppress T-cell proliferation in vitro. C57BL/6 female mice with pancreatic tumors were treated with FOLFIRINOX with or without recombinant G-CSF to directly assess the role of G-CSF on induction of immunosuppressive neutrophils.
RESULTS
Patients receiving FOLFIRINOX with pegfilgrastim had increased serum G-CSF that correlated with an induction of granulocytic MDSCs. This increase was not observed in patients receiving gemcitabine/n(ab)paclitaxel without pegfilgrastim. Interleukin-18 also significantly increased in serum on FOLFIRINOX treatment. Patient serum could induce MDSCs as determined by in vitro functional assays, and this suppressive effect increased with on-treatment serum. Induction of MDSCs in vitro could be recapitulated by addition of recombinant G-CSF to healthy serum, indicating that G-CSF is sufficient for MDSC differentiation. In mice, neutrophils isolated from spleen of G-CSF-treated mice were significantly more capable of suppressing T-cell proliferation.
CONCLUSIONS
Pegfilgrastim use contributes to immune suppression in both humans and mice with pancreatic cancer. These results suggest that use of recombinant G-CSF as supportive care, while critically important for mitigating neutropenia, may complicate efforts to induce antitumor immunity.
Topics: Animals; Female; Humans; Mice; Antineoplastic Combined Chemotherapy Protocols; Gemcitabine; Granulocyte Colony-Stimulating Factor; Immunosuppression Therapy; Leukocytes, Mononuclear; Mice, Inbred C57BL; Neutropenia; Paclitaxel; Pancreatic Neoplasms; Recombinant Proteins; Tumor Microenvironment
PubMed: 37344102
DOI: 10.1136/jitc-2022-006589 -
Atencion Primaria 2021To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and...
OBJECTIVE
To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and metamizole contains accurate and necessary information to protect patients from the presentation of this adverse reaction (AR) and if the official documentation of medicines containing metamizole for doctors, pharmacists and the general population conforms to the guidelines of the AEMPS to reduce this risk.
SETTING AND PARTICIPANTS
Drug safety update, bibliographic search, information at the European Medicines Agency on metamizole drugs marketed in Spain, technical datasheets, leaflets, Bot PLUS Health Information Database and Catalog of Pharmaceutical Specialties. Notification of 4cases of agranulocytosis due to metamizole after the drug safety update was issued.
MAIN INTERVENTIONS AND MEASUREMENTS
Comparison of the key points of the drug safety update and official documents on metamizole with the bibliography. Description of the 4cases of agranulocytosis due to metamizole and application of the causality and severity algorithm.
RESULTS
The drug safety update contains omissions and contradiction in respect to the bibliography and the actual use of metamizole in healthcare practice. The official documents show a lack of updating, unapproved indications and doses higher than those recommended. The drug safety update has not stopped the presentation of cases of agranulocytosis due to metamizole.
CONCLUSIONS
The AEMPS drug safety update can be improved and it is necessary to update the official information documents on metamizole for health professionals and patients in order to decrease the risk of agranulocytosis.
Topics: Agranulocytosis; Anti-Inflammatory Agents, Non-Steroidal; Databases, Factual; Dipyrone; Humans; Spain
PubMed: 33823317
DOI: 10.1016/j.aprim.2021.102047 -
Journal of Gastrointestinal Surgery :... Dec 2021Surgeons encounter neutropenic patients through elective or emergency consultation with increasing regularity. As medical management continues to extend the lives of... (Review)
Review
Surgeons encounter neutropenic patients through elective or emergency consultation with increasing regularity. As medical management continues to extend the lives of patients with benign hematologic diseases, hematologic malignancies, solid malignancies, or iatrogenic neutropenia, more patients are presenting with infectious complications caused and/or complicated by their neutropenia. This leaves surgeons in the difficult position of managing medically fragile patients with unusual presentations of common disease processes. These patients often fall outside of classical guidelines and treatment pathways. Many studies addressing these issues are retrospective and non-randomized. Here, we review common emergency gastrointestinal surgery scenarios and their management in the setting of a neutropenic patient. While biliary disease, appendicitis, anorectal disease, and perforations will be covered in detail, an extensive appreciation of a patient's medical or oncologic disease course and appropriate utilization of consultants such as interventional radiology, gastroenterology, and hematology is often necessary.
Topics: Appendicitis; Emergencies; Humans; Immunocompromised Host; Neutropenia; Retrospective Studies
PubMed: 34506017
DOI: 10.1007/s11605-021-05116-9 -
British Journal of Pharmacology Jun 2022Chemotherapy-induced immune-suppression is a common, but potential detrimental, adverse reaction in patients undergoing treatment for cancer and strategies with capacity... (Review)
Review
Chemotherapy-induced immune-suppression is a common, but potential detrimental, adverse reaction in patients undergoing treatment for cancer and strategies with capacity to boost the immune cell populations are needed. Physical exercise training is a potent regulator of immune cell viability and function and may serve as a viable, non-pharmacological prophylactic strategy in addition to the current pharmacological management by, for example, granulocyte-colony stimulating factor (G-CSF). Here, we review the mechanistic evidence linking exercise training to haematopoietic function and subsequent possible amelioration of chemotherapy-related neutropenia. First, we briefly describe neutrophil regulation and management of neutropenia in cancer patients. Second, we summarize the effect of acute and chronic exercise training on neutrophils and their progenitors, and finally, we outline the current clinical evidence of exercise interventions in ongoing anti-cancer treatment in regard to neutropenia incidence, treatment tolerance and related outcomes. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.
Topics: Exercise; Humans; Neutropenia
PubMed: 32449810
DOI: 10.1111/bph.15141 -
Science (New York, N.Y.) Mar 2023Mutations in the 3' to 5' RNA exonuclease USB1 cause hematopoietic failure in poikiloderma with neutropenia (PN). Although USB1 is known to regulate U6 small nuclear RNA...
Mutations in the 3' to 5' RNA exonuclease USB1 cause hematopoietic failure in poikiloderma with neutropenia (PN). Although USB1 is known to regulate U6 small nuclear RNA maturation, the molecular mechanism underlying PN remains undetermined, as pre-mRNA splicing is unaffected in patients. We generated human embryonic stem cells harboring the PN-associated mutation c.531_delA in USB1 and show that this mutation impairs human hematopoiesis. Dysregulated microRNA (miRNA) levels in USB1 mutants during blood development contribute to hematopoietic failure, because of a failure to remove 3'-end adenylated tails added by PAPD5/7. Modulation of miRNA 3'-end adenylation through genetic or chemical inhibition of PAPD5/7 rescues hematopoiesis in USB1 mutants. This work shows that USB1 acts as a miRNA deadenylase and suggests PAPD5/7 inhibition as a potential therapy for PN.
Topics: Humans; Hematopoiesis; Human Embryonic Stem Cells; MicroRNAs; Neutropenia; Phosphoric Diester Hydrolases; Mutation
PubMed: 36862787
DOI: 10.1126/science.abj8379 -
Blood Feb 2022
Topics: DiGeorge Syndrome; Humans; Neutropenia
PubMed: 35113147
DOI: 10.1182/blood.2021012606 -
BMC Infectious Diseases Oct 2023The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse... (Review)
Review
BACKGROUND
The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse effects are hypokaliemia and hypernatremia. We describe a case of agranulocytosis, a rarely described side effect that may be fatal.
CASE PRESENTATION
A 45 year-old woman was admitted to the intensive care unit for post-surgical meningitis following meningioma resection. Meropenem and vancomycin were first introduced. A DRESS-syndrom with meropenem was suspected. Neutropenia was diagnosed three days after the introduction of parenteral fosfomycin and agranulocytosis four days later. Eosinophilia was also observed. A bone marrow aspiration was performed showing a disappearance of the neutrophil granulocyte line and a significant eosinophilia. Meropenem was discontinued. Fosfomycin was maintained and filgrastim was added. As filgrastim had no effect, the relationship with fosfomycin was suspected, so it was then withheld. An increase of the neutrophil count was observed. Because of the complexity of the case, the unfavorable course of the illness and the urgent need for revision surgery, a rechallenge with fosfomycin was done followed by a decrease of the neutrophil count.
CONCLUSION
This is the third paper reporting agranulocytosis induced by fosfomycin, and the first detailed description of a case. Based on chronological and semiological criteria and bibliographic data, the event was qualified as probable with the Naranjo adverse drug probability scale. Literature data is scarce. The summary of product characteristics mentions that only a few cases of transient neutropenia and agranulocytosis have been reported. An analysis of the FDA Adverse Event Reporting System Database highlighted a higher than expected frequency of agranulocytosis in patients treated with fosfomycin. Parenteral fosfomycin is often used in patients receiving other medications, so that it is rarely the only suspect. In our case, the results of the bone marrow aspiration, the sudden drop of the neutrophil count with concomitant eosinophilia and the absence of improvement despite the dose decrease, point towards an immuno-allergic mechanism. However, the overlap between the suspected DRESS induced by meropenem and the agranulocytosis do not allow to conclude with certainty on the causality. Awareness should be raised about this side effect.
Topics: Female; Humans; Middle Aged; Fosfomycin; Filgrastim; Meropenem; Neutropenia; Anti-Bacterial Agents; Drug-Related Side Effects and Adverse Reactions; Eosinophilia
PubMed: 37833638
DOI: 10.1186/s12879-023-08652-8 -
Tijdschrift Voor Psychiatrie 2023Clozapine is the most effective treatment for people with treatment-resistant schizophrenia. However, it is prescribed less often than guidelines indicate. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Clozapine is the most effective treatment for people with treatment-resistant schizophrenia. However, it is prescribed less often than guidelines indicate.
AIM
To personalize clozapine treatment, we investigated the efficacy of clozapine as first- or second-line treatment and investigated whether there are factors that were associated with efficacy and side effects.
METHOD
We collected a unique cohort of over 800 clozapine users diagnosed with a schizophrenia spectrum disorder. We meta-analyzed factors that were associated with response during clozapine treatment. Additionally, we conducted genetic association analyses to investigate the relations between side effects and symptom severity during clozapinetreatment.
RESULTS
From our meta-analyses, we found that clozapine was more effective when used as a first- or second-line treatment. Furthermore, we found that younger age, less negative symptoms and the paranoid subtype of schizophreniawere associated with a better clozapine response. Several specific locations on genes (loci) were associated with clozapine-induced agranulocytosis and neutropenia, while polygenic risk scores were associated with symptom severity.
CONCLUSION
We found that clozapine could be effective earlier in treatment and identified factors that could aid the prediction of< response to clozapine treatment in the future. These finding could contribute to the start of a personalized clozapine treatment.
Topics: Humans; Antipsychotic Agents; Clozapine; Neutropenia; Precision Medicine; Schizophrenia
PubMed: 36912056
DOI: No ID Found